Important Anti-aging Protein Studied by Harvard Team

Back in the 1950s in a weird, vampiric experiment, scientists first showed that connecting the circulatory systems of old and young mice seems to rejuvenate the more elderly animals. A handful of labs have recently been racing to find factors in young blood that may explain this effect. Now, a Harvard University group that claims to have found one such antiaging protein has published a study countering critics who dismissed the work on the molecule as flawed.

Harvard stem cell biologist Amy Wagers, cardiologist Richard Lee of the Harvard-affiliated Brigham and Women?s Hospital in Boston, and their colleagues claim that a specific protein, GDF11, may explain young blood?s beneficial effects. They have reported that blood levels of GDF11 drop in mice as the animals get older and that injecting old mice with GDF11 can partially reverse age-related thickening of the heart. In two papers last year in Science, Wagers and collaborators also reported that GDF11 can rejuvenate the rodents? muscles and brains.

Last May, however, a group led by muscle disease researcher David Glass of the Novartis Institutes for Biomedical Research in Cambridge, Massachusetts, reported that the antibody the Harvard team used to measure levels of GDF11 also detected myostatin (also known as GDF8), a similar protein that hinders muscle growth. The Novartis group concluded from a different assay that GDF11 levels in blood actually rise with age in rats and people. And in their lab, GDF11 injections inhibited muscle regeneration in young mice.

Now, the Wagers and Lee group says the assay Novartis used to detect GDF11 and GDF8 was itself flawed. They found that the main protein detected by the antibody test is immunoglobulin, another protein that rises in blood level with age. Mice lacking the gene for immunoglobulin tested negative for the active form of GDF11/8 that the Novartis assay was thought to reveal, they report today online in Circulation Research.

?They actually had very consistent findings to ours with respect to the blood levels of GDF11/8 with the antibody we all used,? Wagers says. But ?their interpretation was confused by this case of mistaken identity.? A recently published study by University of California, San Francisco, researchers finding that GDF11/8 blood levels decline with age in people and are low in those with heart disease supports the contention that GDF11 has an antiaging role, her paper notes.

The Harvard team?s paper also disputes a recent study in which cardiac physiologist Steven Houser?s group at Temple University in Philadelphia, Pennsylvania, found that GDF11 injections have no effect on heart thickness in older mice. The problem, according to Wagers, is that commercially purchased GDF11 can vary in the actual level and activity of protein. ?It wasn?t something that affected us early on, but we figured out it was an issue,? she says. That lot-to-lot variability likely explains why the Houser group didn?t see any effects from GDF11 at the same apparent dose the Harvard group reported using, she adds. (Lee says his group now suspects that the dose was higher than they realized.)

To back up their earlier results, Wagers and collaborators again show in the new paper that daily GDF11 injections can shrink heart muscle in both old and new mice. But this time they note another observation: The mice also lost weight. ?We don?t have much insight into that right now, but we?re looking into it,? Wagers says. She says the findings suggest that as with other hormones, GDF11 may have ?a therapeutic window? for beneficial effects?too much may cause harm.

Houser says he agrees that one of the Novartis team?s assays for GDF11 was probably detecting immunoglobulin. But Houser notes that the group also used a different assay to detect GDF11 and that isn?t challenged by the new paper. (David Glass makes the same point.) Sorting out what role GDF11 may play in aging is important, Houser adds. ?I’m going to be 65 in a couple months. I’d love to have something that improves my heart, brain, and muscle function,? Houser says. ?I think the field is going to figure this out and this is another piece of the puzzle.?

The Science of Happiness

Exercising, meditating, scouring self-help books… we go out of our way to be happy, but do we really know what happiness is?

Wataru Sato and his team at Kyoto University have found an answer from a neurological perspective. Overall happiness, according to their study, is a combination of happy emotions and satisfaction of life coming together in the precuneus, a region in the medial parietal lobe that becomes active when experiencing consciousness.

People feel emotions in different ways; for instance, some people feel happiness more intensely than others when they receive compliments. Psychologists have found that emotional factors like these and satisfaction of life together constitutes the subjective experience of being “happy.” The neural mechanism behind how happiness emerges, however, remained unclear. Understanding that mechanism, according to Sato, will be a huge asset for quantifying levels of happiness objectively.

Sato and his team scanned the brains of research participants with MRI. The participants then took a survey that asked how happy they are generally, how intensely they feel emotions, and how satisfied they are with their lives.

Their analysis revealed that those who scored higher on the happiness surveys had more grey matter mass in the precuneus. In other words, people who feel happiness more intensely, feel sadness less intensely, and are more able to find meaning in life have a larger precuneus.

“Over history, many eminent scholars like Aristotle have contemplated what happiness is,” lead author Wataru Sato said. “I’m very happy that we now know more about what it means to be happy.”

So how does that help us? Sato is hopeful about the implications this has for happiness training.

“Several studies have shown that meditation increases grey matter mass in the precuneus. This new insight on where happiness happens in the brain will be useful for developing happiness programs based on scientific research,” he said.

Source Reference:

Wataru Sato, Takanori Kochiyama, Shota Uono, Yasutaka Kubota, Reiko Sawada, Sayaka Yoshimura, Motomi Toichi. The structural neural substrate of subjective happiness. Scientific Reports, 2015; 5: 16891 DOI: 10.1038/srep16891

Neuron Research Breakthrough

Aging insidiously leaves its mark on our brains.

With age, our well-oiled neuronal machinery slowly breaks down: gene expression patterns turn wacky, the nuclear membrane disintegrates, and neatly organized molecules inside the cells break out of their segregated compartments, turning the intracellular environment into a maladaptive, muddled molecular soup.

Yet the aging phenomenon has been very tough to study. Historically, scientists relied on fast-aging animal models ? from fruit flies to primitive worms to mice ? to tease out the biological mechanisms of aging, especially for tissues that are hard to biopsy from patients, including the brain.

Despite the value of these reductionist models, many life-lengthening treatments fail in clinical trials, and the leap from flies to mice to men remains insurmountable.

With the rise of induced pluripotent stem cell (iPSC) technology, scientists have been able to transform patients? skin cells into iPSCs, which can then be coaxed into neurons for further study.

It?s a powerful technique: iPSCs derived from patients with Parkinson?s disease, for example, contain the same genetic underpinnings of the disease, which let scientists cheaply and efficiently test out theories and potential drug treatments?on human cells within the tightly controlled environment of a culture dish.

But the conversion process essentially turns back the clock: because iPSCs resemble early stage embryonic development, even when taken from an elder donor, they ? and the neurons generated from them ? lose their ?aged? signature. Previous research found that their epigenetic landscapes, which dictate what genes are expressed where via small chemical attachments to the DNA, are reset to match that of a younger cell?s profile during the reprogramming process.

For example, genes that promote cell division are jacked up, whereas genes involved in inflammation ? a strong correlate of aging ? are tuned down. This discrepancy hardly makes them a good model of their aged donors.

It?s a thorny problem that?s plagued the field for decades. But now, published last week in Cell Stem Cell, a team led by Salk Institute professor Dr. Fred ?Rusty? Gage has offered a clever solution.

The answer is to eschew iPSCs altogether, and take the road less traveled.

Using a method first discovered a few years ago at Stanford University, the team realized that with a series of careful biochemical tweaks, they could directly coax skin cells into fully functional neurons. Since these ?induced neurons? skipped the embryonic stage, they reasoned, maybe their age counters were not reset.

No one knew if and how cells created in this way differed from neurons that naturally aged in the human brain, says lead author Dr. Jermone Mertens.

To find out, the team took skin biopsies from 19 volunteers aged from infancy to 89 years old, and transformed those skin cells into neurons using both the iPSC method and the direct conversion approach.

They then compared these ?test tube neurons? to neurons obtained from autopsies of age-matched controls by looking at their transcriptomics ? that is, a bird?s eye view of gene expression patterns that change with age.

As expected, iPSC-generated neurons lost their life history, reverting back to a baby-like state.

In stark contrast, neurons generated by direct conversion significantly differed in their transcriptomes based on the donor?s age. ?They actually show changes in gene expression that have been previously implicated in brain aging,? said Mertens.

It?s a first, and it could be a game changer.

He pointed to a protein called RanBP17, which shuttles proteins in-and-out of the nucleus. The decline of RanBP17 was previously hypothesized to play a role in brain aging, but the theory was difficult to model in animals. However, to the team?s excitement, this abnormal decrease was recapitulated in neurons directly converted from older patients.

Other cellular assays also showed that the lab-grown neurons retained their telltale signs of aging. With age, the fragile membrane that separates the nucleus from other cellular component begins to fail, and proteins ? no longer confined to their physiological working space ? run amok.

This process could lead to aging or increase our susceptibility to age-related neurodegenerative disorders, but we don?t know, said Martens. He?s eager to put the new system to use. With this new culture system, we can now directly test these ideas, Martens said.

?The results are obviously going to have an impact,? agrees Dr. John Gearhart, an expert in regenerative medicine at the University of Pennsylvania, who wasn?t involved in the study.

Although the team only tried their cell-transforming method in neurons, Gage expects it to work for other organs as well, allowing scientists to create aged heart or liver cells. The technique could also be expanded to highly-structured 3D cultures such as organoids, and used to model aging human organs.

“We expect that the paradigm of direct conversion into age-equivalent cells can be very important for future studies of age-related diseases,” said Gage.

Lack of Sleep Impairs Stem Cell Therapy

An unexpected factor may be influencing stem cell transplants, suggests a new study by researchers at the Stanford University School of Medicine. They found that a sleep deprived donor has a huge effect on the ability of blood and immune system stem cells to migrate to their proper spots in the bone marrow of a recipient.

The research was conducted on laboratory mice, but may have implications for human stem cell transplants. Thousands of procedures often referred to as bone marrow transplants (but more accurately called hematopoietic stem cell transplants) are performed every year.

In the experiment, a sleep deficit of only four hours could affect by as much as 50 percent the ability of stem cells to migrate successfully.

?Considering how little attention we typically pay to sleep in the hospital setting, this finding is troubling,? said Dr. Asya Rolls, an assistant professor at the Israel Institute of Technology, in a statement. ?We go to all this trouble to find a matching donor, but this research suggests that if the donor is not well-rested it can impact the outcome of the transplantation. However, it?s heartening to think that this is not an insurmountable obstacle; a short period of recovery sleep before transplant can restore the donor?s cells? ability to function normally.?

Rolls is co-lead author of the study along with Dr. Wendy Pang, a postdoctoral scholar at Stanford, and Dr. Ingrid Ibarra, the assistant director of the Stanford Cardiovascular Institute.

The team conducted research comparing mice who had been gently handled for four hours to prevent sleep with mice who were well-rested. They collected stem cells from the bone marrow of both groups of mice and injected them into 12 mice who had received what would normally be a deadly dose of radiation. The recipient mice also got a dose of their own bone marrow cells, so it would be possible to track the abilities of the donated cells in relation.

The researchers assessed the prevalence of myeloid cells, a type of immune cell, at both eight and 16 weeks after the transplant. They found that stem cells from the well-rested mice made up about 26 percent of myeloid cells over time, but stem cells from sleep deprived donors made up only about 12 percent of the recipient?s myeloid cells.

The team also looked at the ability of the stem cells to migrate properly from the blood into the bone marrow. After 12 hours, 3.3 percent of the stem cells from rested mice had found their way to the bone marrow, compared to only 1.7 percent of stem cells from sleepy mice.

Rolls and her colleagues found that the effects of sleep deprivation could be reversed by catching only a couple hours of sleep.

?Everyone has these stem cells, and they continuously replenish our blood and immune system,? Rolls said. ?We still don?t know how sleep deprivation affects us all, not just bone marrow transplant donors. The fact that recovery sleep is so helpful only emphasizes how important it is to pay attention to sleep.?

How Stem Cells Are Affected By Their Surroundings

A Johns Hopkins University biologist has led a research team reporting progress in understanding the shape-shifting ways of stem cells, which have vast potential for medical research and disease treatment.

In a research paper published in Cell Reports on Oct. 13, Xin Chen, an associate professor of biology in the university’s Krieger School of Arts and Sciences, and her six co-authors report on how stem cells are affected by their immediate surroundings. The scientists found that an enzyme present in the spot where stem cells are found can help nurture a greater abundance of these cells by sustaining them in their original state, and by promoting other cells to lose their specialized traits and transform into stem cells.

The results show that the enzyme aminopeptidase in the stem cell niche?in this case, the area where stem cells are found in the testicular tissue in fruit flies?plays a role in both of these functions. How the niche itself plays this role, however, remains unclear.

That the enzyme in that spot promotes more specialized cells to become like stem cells “suggests that this change of cell fate needs cues from where stem cells normally reside, but not randomly,” said Chen, the principal investigator. “These results have medical implications because if this cell fate change could happen randomly, it may lead to diseases such as cancers.”

That’s because there’s a delicate balance to be struck in managing the proliferation of undifferentiated stem cells in tissue, Chen said. Too few can cause tissue deterioration, too many can promote tumors.

The study focused on fruit flies in part because they share with humans about three-quarters of the genes that cause disease, making them a fine research model. The work on this paper focused on the testis because stem cells are found there in both fruit flies and humans.

Stem cells are found in humans in an array of tissues, including skin, blood vessels, teeth, heart, brain, and liver.

Because they can develop from their original state into specialized or differentiated cells, stem cells have long held out the promise of being used to replace damaged organs and muscle. Stem cells have been used to treat illness in limited ways for decades, including transplantation from bone marrow.

However, their application could be much wider with reliable techniques to control how they take on specialized functions, how they can revert to their stem state, and in some instances, how they proliferate in their original state to form potentially dangerous tumors.

One question now is whether the activity of the niche and of the enzyme reported in this research can be harnessed to manipulate stem cells to differentiate in useful ways. There’s a lot of work yet to be done, Chen said.

“How cells become different, it’s very important to understand that,” Chen said.

Chen’s six collaborators on this paper were Cindy Lim, who earned her doctorate at Johns Hopkins and now works for the U.S. Food and Drug Administration; Lijuan Feng of the Johns Hopkins University Department of Biology; Shiv Gandhi and Sinisa Urban of the Howard Hughes Medical Institute, Department of Molecular Biology and Genetics at the Johns Hopkins University School of Medicine; and Martin L. Biniossek and Oliver Schilling of the Institute of Molecular Medicine and Cell Research at the University of Freiburg.

Human Kidney Grown in the Lab by Scientists

Researchers in Melbourne and Brisbane have successfully grown a human ‘mini-kidney’ from stem cells.

Published in the journal Nature, the results have significant implications for medical research, as the mini-organ mimics normal kidney development.

It means laboratory-grown kidneys can be used for drug testing and potentially the bioengineering of replacement kidneys for patients with renal failure as they can be grown from any person using cells such as skin or blood.

It also opens the door for cell therapy and other new treatments for kidney disease – not to mention giving researchers a chance to grow ‘kidney models’ to learn more about how the human kidney forms normally.

“For us it’s a pretty exciting advance,” said stem cell biologist Melissa Little, of the Murdoch Childrens Research Institute.

“This organ is making its own blood vessels, it’s making it’s own tubules for filtering and cleaning the blood, so it’s really a very complex structure,” she said of the kidney, which was observed three weeks after creation.

An author on the paper, Professor Little said it was equally important to learn how healthy and diseased kidneys functioned but that ethical reasons often limited research on human kidneys. Instead mice were used. However, she said while the mouse kidney was similar to humans, it was structurally different.

“Now for the first time we have a chance to ask what is different between a human and a mouse kidney because we don’t study human kidneys for obvious reasons,” she said. “From a research point of view it is going to tell us a great deal more than we knew before.”

About half the children with kidney disease had inherited the condition via a genetic mutation. Being able to grow a kidney using a patient’s stem cells meant a diseased kidney could be grown to test a patient’s response to treatment before drugs were administered.

The breakthrough follows Professor Little’s team’s first creation of a mini-kidney in 2013, which was able to form two cell-types.

This kidney, grown in collaboration with colleagues from Melbourne University and the University of Queensland, is different. No longer than a centimetre, it features up to 12 types of cell normally found in the human body making it equivalent to a foetal kidney. An adult kidney has around 20 cell types and is the size of a large softball.

It was also created using stem cells made from adult skin, rather than embryonic stem cells which were used in the 2013 kidney.

Life Extension Genetic Research

Following an exhaustive, ten-year effort, scientists at the Buck Institute for Research on Aging and the University of Washington have identified 238 genes that, when removed, increase the replicative lifespan of S. cerevisiae yeast cells. This is the first time 189 of these genes have been linked to aging. These results provide new genomic targets that could eventually be used to improve human health. The research was published online on October 8th in the journal Cell Metabolism.

“This study looks at aging in the context of the whole genome and gives us a more complete picture of what aging is,” said Brian Kennedy, PhD, lead author and the Buck Institute’s president and CEO. “It also sets up a framework to define the entire network that influences aging in this organism.”

The Kennedy lab collaborated closely with Matt Kaeberlein, PhD, a professor in the Department of Pathology at the University of Washington, and his team. The two groups began the painstaking process of examining 4,698 yeast strains, each with a single gene deletion. To determine which strains yielded increased lifespan, the researchers counted yeast cells, logging how many daughter cells a mother produced before it stopped dividing.

“We had a small needle attached to a microscope, and we used that needle to tease out the daughter cells away from the mother every time it divided and then count how many times the mother cells divides,” said Dr. Kennedy. “We had several microscopes running all the time.”

These efforts produced a wealth of information about how different genes, and their associated pathways, modulate aging in yeast. Deleting a gene called LOS1 produced particularly stunning results. LOS1 helps relocate transfer RNA (tRNA), which bring amino acids to ribosomes to build proteins. LOS1 is influenced by mTOR, a genetic master switch long associated with caloric restriction and increased lifespan. In turn, LOS1 influences Gcn4, a gene that helps govern DNA damage control.

“Calorie restriction has been known to extend lifespan for a long time.” said Dr. Kennedy. “The DNA damage response is linked to aging as well. LOS1 may be connecting these different processes.”

A number of the age-extending genes the team identified are also found in C. elegans roundworms, indicating these mechanisms are conserved in higher organisms. In fact, many of the anti-aging pathways associated with yeast genes are maintained all the way to humans.

The research produced another positive result: exposing emerging scientists to advanced lab techniques, many for the first time.

“This project has been a great way to get new researchers into the field,” said Dr. Kennedy. “We did a lot of the work by recruiting undergraduates, teaching them how to do experiments and how dedicated you have to be to get results. After a year of dissecting yeast cells, we move them into other projects.”

Though quite extensive, this research is only part of a larger process to map the relationships between all the gene pathways that govern aging, illuminating this critical process in yeast, worms and mammals. The researchers hope that, ultimately, these efforts will produce new therapies.

“Almost half of the genes we found that affect aging are conserved in mammals,” said Dr. Kennedy. “In theory, any of these factors could be therapeutic targets to extend healthspan. What we have to do now is figure out which ones are amenable to targeting.”

Human Brain Stem Cells Discovery

The human cerebral cortex contains 16 billion neurons, wired together into arcane, layered circuits responsible for everything from our ability to walk and talk to our sense of nostalgia and drive to dream of the future. In the course of human evolution, the cortex has expanded as much as 1,000-fold, but how this occurred is still a mystery to scientists.

Now, researchers at UC San Francisco have succeeded in mapping the genetic signature of a unique group of stem cells in the human brain that seem to generate most of the neurons in our massive cerebral cortex.

The new findings, published Sept. 24 in the journal Cell, support the notion that these unusual stem cells may have played an important role in the remarkable evolutionary expansion of the primate brain.

?We want to know what it is about our genetic heritage that makes us unique,? said Arnold Kriegstein, MD, PhD, professor of developmental and stem cell biology and director of the Eli and Edyth Broad Center of Regeneration Medicine and Stem Cell Research at UCSF. ?Looking at these early stages in development is the best opportunity to understand our brain?s evolution.?

Building a Brain from the Inside Out

The grand architecture of the human cortex, with its hundreds of distinct cell types, begins as a uniform layer of neural stem cells and builds itself from the inside out during several months of embryonic development.

Until recently, most of what scientists knew about this process came from studies of model organisms such as mice, where nearly all neurons are produced by stem cells called ventricular radial glia (vRGs) that inhabit a fertile layer of tissue deep in the brain called the ventricular zone (VZ). But recent insights suggested that the development of the human cortex might have some additional wrinkles.

In 2010, Kriegstein?s lab discovered a new type of neural stem cell in the human brain, which they dubbed outer radial glia (oRGs) because these cells reside farther away from the nurturing ventricles, in an outer layer of the subventricular zone (oSVZ). To the researchers? surprise, further investigations revealed that during the peak of cortical development in humans, most of the neuron production was happening in the oSVZ rather than the familiar VZ.

oRG stem cells are extremely rare in mice, but common in primates, and look and behave quite differently from familiar ventricular radial glia. Their discovery immediately made Kriegstein and colleagues wonder whether this unusual group of stem cells could be a key to understanding what allowed primate brains to grow to their immense size and complexity.

?We wanted to know more about the differences between these two different stem cell populations,? said Alex Pollen, PhD, a postdoctoral researcher in Kriegstein?s lab and co-lead author of the new study. ?We predicted oRGs could be a major contributor to the development of the human cortex, but at first we only had circumstantial evidence that these cells even made neurons.?

Outsider Stem Cells Make Their Own Niche

In the new research, Pollen and co-first author Tomasz Nowakowski, PhD, also a postdoctoral researcher in the Kriegstein lab, partnered with Fluidigm Corp. to develop a microfluidic approach to map out the transcriptional profile ? the set of genes that are actively producing RNA ? of cells collected from the VZ and SVZ during embryonic development.

They identified gene expression profiles typical of different types of neurons, newborn neural progenitors and radial glia, as well as molecular markers differentiating oRGs and vRGs, which allowed the researchers to isolate these cells for further study.

The gene activity profiles also provided several novel insights into the biology of outer radial glia. For example, researchers had previously been puzzled as to how oRG cells could maintain their generative vitality so far away from the nurturing VZ. ?In the mouse, as cells move away from the ventricles, they lose their ability to differentiate into neurons,? Kriegstein explained.

But the new data reveals that oRGs bring a support group with them: The cells express genes for surface markers and molecular signals that enhance their own ability to proliferate, the researchers found.

?This is a surprising new feature of their biology,? Pollen said. ?They generate their own stem cell niche.?

The researchers used their new molecular insights to isolate oRGs in culture for the first time, and showed that these cells are prolific neuron factories. In contrast to mouse vRGs, which produce 10 to 100 daughter cells during brain development, a single human oRG can produce thousands of daughter neurons, as well as glial cells?non-neuronal brain cells increasingly recognized as being responsible for a broad array of maintenance functions in the brain.

New Insights into Brain Evolution, Development and Disease

The discovery of human oRGs? self-renewing niche and remarkable generative capacity reinforces the idea that these cells may have been responsible for the expansion of the cerebral cortex in our primate ancestors, the researchers said.

The research also presents an opportunity to greatly improve techniques for growing brain circuits in a dish that reflect the true diversity of the human brain, they said. Such techniques have the potential to enhance research into the origins of neurodevelopmental and neuropsychiatric disorders such as microcephaly, lissencephaly, autism and schizophrenia, which are thought to affect cell types not found in the mouse models that are often used to study such diseases.

The findings may even have implications for studying glioblastoma, a common brain cancer whose ability to grow, migrate and hack into the brain?s blood supply appears to rely on a pattern of gene activity similar to that now identified in these neural stem cells.

?The cerebral cortex is so different in humans than in mice,? Kriegstein said. ?If you?re interested in how our brains evolved or in diseases of the cerebral cortex, this is a really exciting discovery.?

The study represents the first salvo of a larger BRAIN Initiative-funded project in Kriegstein?s lab to understand the thousands of different cell types that occupy the developing human brain

?At the moment, we simply don?t have a good understanding of the brain?s ?parts list,?? Kriegstein said, ?but studies like this are beginning to give us a real blueprint of how our brains are built.?

Stem Cells Responsible for Flatworm’s Regenerative Capabilities

After sequencing the genome of flatworms (Macrostomum lignano), researchers from Cold Springs Harbor Laboratory (CSHL) have concluded that it can regenerate parts of its entire body ? with the exception of its brain. According to the scientists, this has potential applications in stem cell research.

“This and other regenerating flatworms have the same kind of pathway operating in stem cells that is responsible for their remarkable regenerative capabilities.” Gregory Hannon, a CSHL professor, said in a news release. “As we started to try to understand the biology of these stem cells, it very quickly became clear that we needed information about the genetic content of these organisms.”

As certain species grow, base cells called stem cells develop into many different cell types. They also act as an internal repair system, dividing and replenishing other cells as needed, similar to how flatworms regenerate body parts that are injured.

Hannon was studying an important pathway in mammalian reproductive tissues when M. lignano caught his eye. When his researchers took a closer look, they found that the flatworm had a very complex genome with repetitive elements, which made it hard to assemble. This required the use of long-read, or high-quality, sequencing technology.

“At the genomic level it has almost no relationship to anything else that’s ever been sequenced. It’s very strange and unique in that sense,” notes Michael Schatz, a CSHL associate professor.

“The worms are just like floating sacks full of stem cells, so they’re very easily accessible,” said Kaja Wasik, the study’s lead author who conducted the work as a Ph.D. student in Hannon’s lab. “From what we looked at, it looks like many of the developmental pathways that are present in humans are also present in the worms, and we can now study whether they potentially could be involved in regeneration.”

M. lignano aids in stem cell researcher because it is small, has simple tissues, is transparent and uses sexual reproduction, the researchers noted. Sequencing the flatworm’s genome is a stepping stone in understanding exactly how its cells are able to regenerate.

Their findings were recently published in the journal Proceedings of the National Academy of Sciences.

Porous Hydrogel May Improve Stem Cell Therapy

Possible stem cell therapies often are limited by low survival of transplanted stem cells and the lack of precise control over their differentiation into the cell types needed to repair or replace injured tissues. A team led by David Mooney, a core faculty member at Harvard?s Wyss Institute, has now developed a strategy that has experimentally improved bone repair by boosting the survival rate of transplanted stem cells and influencing their cell differentiation. The method embeds stem cells into porous, transplantable hydrogels.

In addition to Mooney, the team included Georg Duda, a Wyss associate faculty member and director of the Julius Wolff Institute for Biomechanics and Musculoskeletal Regeneration at Charit? ? Universit?tsmedizin in Berlin, and Wyss Institute founding director Donald Ingber. The team published its findings in today?s issue of Nature Materials. Mooney is also the Robert P. Pinkas Family Professor of Bioengineering at the Harvard John A. Paulson School of Engineering and Applied Sciences.

Stem cell therapies have potential for repairing many tissues and bones, or even for replacing organs. Tissue-specific stem cells can now be generated in the laboratory. However, no matter how well they grow in the lab, stem cells must survive and function properly after transplantation. Getting them to do so has been a major challenge for researchers

Mooney?s team and other researchers have identified specific chemical and physical cues from the stem cell niche (the area in which stem cells survive and thrive with support from other cell types and environmental factors) to promote stem cell survival, multiplication and maturation into tissue. Whereas chemical signals that control stem cell behavior are increasingly understood, much less is known about the mechanical properties of stem cell niches. Stem cells like those present in bone, cartilage, or muscle cultured in laboratories, however, have been found to possess mechanosensitivities, meaning they require a physical substrate with defined elasticity and stiffness to proliferate and mature.

?So far these physical influences had not been efficiently harnessed to propel real-world regeneration processes,? said Nathaniel Huebsch, a graduate student who worked with Mooney and who is the study?s first author. ?Based on our experience with mechanosensitive stem cells, we hypothesized that hydrogels could be leveraged to generate the right chemical and mechanical cues in a first model of bone regeneration.?

Two water-filled hydrogels with very different properties are the key to the Mooney team?s method. A more stable, longer-lasting ?bulk gel? is filled with small bubbles of a second, so-called ?porogen? that degrades at a much faster rate, leaving behind porous cavities.

By coupling the bulk gel with a small ?peptide? derived from the extracellular environment of genuine stem cell niches, and mixing it with a tissue-specific stem cell type as well as the porogen, the team can create a bone-forming artificial niche. While the bulk gel provides just the right amount of elasticity plus a relevant chemical signal to coax stem cells to proliferate and mature, the porogen gradually breaks down, leaving open spaces into which the stem cells expand before they naturally migrate out of the gel structure altogether to form actual mineralized bone tissue.

In small-animal experiments conducted so far, the researchers show that a void-forming hydrogel with the correct chemical and elastic properties provides better bone regeneration than transplanting stem cells alone. Of further interest, the maturing stem cells deployed by the hydrogel also induce nearby native stem cells to contribute to bone repair, further amplifying their regenerative effects.

?This study provides the first demonstration that the physical properties of a biomaterial can not only help deliver stem cells but also tune their behavior in vivo,? said Mooney. ?While so far we have focused on orchestrating bone formation, we believe that our hydrogel concept can be broadly applied to other regenerative processes as well.?

The collaborative, cross-disciplinary work was supported by the Harvard University Materials Research Science and Engineering Center (MRSEC), which is funded by the National Science Foundation (NSF).

?This is an exquisite demonstration of MRSEC programs? high impact,? said Dan Finotello, program director at the NSF. ?MRSECs bring together several researchers of varied experience and complementary expertise who are then able to advance science at a considerably faster rate.?